Charting Brachyury-mediated developmental pathways during early mouse embryogenesis

Macarena Lolas, Pablo D.T. Valenzuela, Robert Tjian, Zhe Liu

Research output: Contribution to journalArticlepeer-review

49 Citations (Scopus)

Abstract

To gain insights into coordinated lineage-specification and morphogenetic processes during early embryogenesis, here we report a systematic identification of transcriptional programs mediated by a key developmental regulator - Brachyury. High-resolution chromosomal localization mapping of Brachyury by ChIP sequencing and ChIP-exonuclease revealed distinct sequence signatures enriched in Brachyury-bound enhancers. A combination of genome-wide in vitro and in vivo perturbation analysis and cross-species evolutionary comparison unveiled a detailed Brachyury-dependent gene-regulatory network that directly links the function of Brachyury to diverse developmental pathways and cellular housekeeping programs. We also show that Brachyury functions primarily as a transcriptional activator genome-wide and that an unexpected gene-regulatory feedback loop consisting of Brachyury, Foxa2, and Sox17 directs proper stem-cell lineage commitment during streak formation. Target gene and mRNA-sequencing correlation analysis of the Tc mouse model supports a crucial role of Brachyury in up-regulating multiple key hematopoietic and muscle-fate regulators. Our results thus chart a comprehensive map of the Brachyury-mediated gene-regulatory network and how it influences in vivo developmental homeostasis and coordination.

Original languageEnglish
Pages (from-to)4478-4483
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number12
DOIs
Publication statusPublished - 25 Mar 2014

Keywords

  • Early development
  • Mesoendoderm differentiation
  • Primitive streak

ASJC Scopus subject areas

  • General

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